This 3-part, Phase 1/2 study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and to determine the selected dose of mRNA-3927 in participants with genetically confirmed propionic acidemia (PA). After establishing a dose with an acceptable safety and pharmacodynamic (PD) response for participants ≥1 year of age in Part 1, participants will be enrolled in Part 2 (which will serve as the pivotal study) to allow for determination of the efficacy, safety, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response of mRNA-3927 in infants (\<1 year of age).
Eligibility
Sex
ALL
Min age
—
Max age
—
Healthy volunteers
No
Inclusion Criteria:
Participants ≥1 year of age are eligible to be included in the study only if all of the following criteria apply:
* ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants in Part 1.
* ≥1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1.
* Confirmed diagnosis of PA based on diagnosis by molecular genetic testing via central laboratory (PCCA and/or PCCB mutations).
* Part 2 only: At least one documented MDE in the 12-month period before consent.
Participants \<1 Year of Age :
* Identification by newborn screening shortly after birth or having suspected PA by presenting with a spectrum of metabolic symptoms, and having a sibling diagnosed with PA. Participant may enter the Screening Period while awaiting genetic testing results, provided that all other eligibility criteria are met but would not be enrolled until diagnosis of PA is confirmed.
* For infants in the neonatal intensive care unit (NICU) only: ≥37 weeks gestational age at the time of birth without other conditions/comorbidities that in the opinion of the Investigator may interfere with the interpretation of study results.
* Body weight ≥3 kilograms (kg) at Screening.
* At least 1 documented PA-related event prior to Screening defined as the following criteria:
* Clinical signs of metabolic deterioration consistent with PA (for example, vomiting, not feeding well/poor suck, heavy breathing, lethargy, absence of proper perfusion, abnormal movements including bicycling, abnormal tone, low body temperature, seizure\[s\]), OR
* Meeting the criteria of MDE definition, OR
* Evidence of laboratory abnormalities as evidenced by at least one of the following:
* Metabolic acidosis with elevated anion gap.
* Acute hyperammonemia.
* Neutropenia or thrombocytopenia.
Exclusion Criteria:
Participants of all ages are excluded from the study if during Screening any of the following criteria apply:
* Any individual with laboratory abnormalities considered to be clinically significant (for example, markedly out of range, associated with clinical symptoms) in the Investigator or Sponsor's opinion that could interfere with or limit the participation in the study.
* Estimated glomerular filtration rate (eGFR) \<30 milliliters (mL)/minute/1.73 square meter (m\^2) for participants of all ages receiving chronic dialysis.
* History of organ transplantation or planned organ transplantation during the period of study participation.
* Corrected QT interval (QTc) \>480 milliseconds (ms) using Bazett's correction.
* Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification.
* Pregnant or breastfeeding.
* Other clinically significant conditions that in the Investigator's opinion could interfere with the safety of the participant, the interpretation of study results, or limit the participation in the study.
Primary outcome measure(s)
Part 1: Number of Participants with Treatment-emergent Adverse Event (TEAE), Serious Adverse Events (SAE) and TEAEs Leading to Discontinuation — Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)
Part 2: Change in Annualized Frequency of Clinical Event Committee (CEC)-adjudicated Metabolic Decompensation Events (MDEs) During 12-month Treatment Period With mRNA-3927 Compared to Annualized Frequency of CEC-adjudicated MDE During Pretreatment Period — Pretreatment period (12 months before consent to first mRNA-3927 dose in the study) up to Month 12
Part 3: Number of Participants with TEAEs, SAEs, Adverse Events (AEs) of Special Interest (AESIs) and TEAEs Leading to Discontinuation — Day 1 up to Week 73
Trial sites (35)
Facility
City
Region
Status
UCSD Altman Clinical and Transalational Research Institute Building
Los Angeles
California
Not Yet Recruiting
Ronald Reagan UCLA Medical Center
Los Angeles
California
Recruiting
Lucile Packard Children's Hospital Stanford
Stanford
California
Recruiting
Nicklaus Children's Hospital
Miami
Florida
Not Yet Recruiting
University of South Florida - 12901 Bruce B Downs
Tampa
Florida
Not Yet Recruiting
Ann and Robert H Lurie Childrens Hospital of Chicago
Chicago
Illinois
Recruiting
Johns Hopkins Hospital, Adult Outpatient Clinical Research Unit
Baltimore
Maryland
Completed
Boston Children's Hospital
Boston
Massachusetts
Completed
University of Michigan Hospitals
Ann Arbor
Michigan
Recruiting
Icahn School of Medicine at Mount Sinai - Clinical Research Unit
New York
New York
Recruiting
Duke University Medical System (Duke Health)
Durham
North Carolina
Recruiting
Cincinnati Children's Hospital Medical Center
Cincinnati
Ohio
Completed
University Hospitals Cleveland Medical Center - 11100 Euclid Ave
Cleveland
Ohio
Active Not Recruiting
Children's Hospital of Philadelphia (CHOP)
Philadelphia
Pennsylvania
Recruiting
Texas Children's Hospital
Houston
Texas
Recruiting
Stollery Children's Hospital University of Alberta
Edmonton
Alberta
Recruiting
Hospital For Sick Children
Toronto
Ontario
Recruiting
CHU de Marseille - Hôpital de la Timone
Marseille
France
Active Not Recruiting
Hôpital Necker - Enfants Malades
Paris
France
Recruiting
Fujita Health University Hospital
Toyoake-shi
Aichi-ken
Recruiting
Tohoku University Hospital
Sendai
Miyagi
Recruiting
National Center for Child Health and Development
Tokyo
Japan
Active Not Recruiting
Erasmus MC
Rotterdam
South Holland
Recruiting
Universitair Medisch Centrum Utrecht - PPDS
Utrecht
Netherlands
Active Not Recruiting
King Faisal Specialist Hospital & Research Center - Riyadh
Riyadh
Ar Riya
Active Not Recruiting
King Fahad Medical City
Riyadh
Ar Riya
Not Yet Recruiting
King Abdullah Children's Specialist Hospital
Riyadh
Ar Riya
Not Yet Recruiting
Hospital Sant Joan de Deu - PIN
Esplugues de Llobregat
Barcelona
Active Not Recruiting
Hospital Universitario Cruces
Barakaldo
Biscay
Recruiting
Hospital Universitario 12 de Octubre
Madrid
Spain
Recruiting
Hospital Universitario Virgen del Rocio - PPDS
Seville
Spain
Active Not Recruiting
University Hospital Birmingham NHS Foundation Trust
Birmingham
United Kingdom
Recruiting
Birmingham Children's Hospital
Birmingham
United Kingdom
Completed
Great Ormond Street Hospital for Children NHS Foundation Trust
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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